Ceftazidime-Avibactam Use for Klebsiella pneumoniae Carbapenemase–Producing K. pneumoniae Infections: A Retrospective Observational Multicenter Study

Abstract

Background A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Methods We retrospectively analyzed observational data on the use and outcomes of CAZ-AVI therapy for infections caused by KPC-producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens vs. CAZ-AVI monotherapy. Results The cohort comprised 577 adults with bloodstream infections (BSIs) (n=391) or non-bacteremic infections (nBSIs) involving mainly the urinary tract, lower respiratory tract, intra-abdominal structures. All received treatment with CAZ-AVI alone (n=165) or with one or more other active antimicrobials (n=412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no statistically significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs. 25.0%, P=0.79). In multivariate analysis, mortality was positively associated with the presence at infection onset of septic shock (P=0.002), neutropenia (P <0.001), or an INCREMENT score >8 (P=0.01); with LRTI (P=0.04); and with CAZ-AVI dose adjustment for renal function (P=0.01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P=0.006). All associations remained significant after propensity score adjustment. Conclusions CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug’s seemingly more limited efficacy in LRTIs and the potential survival benefits of prolonging CAZ-AVI infusions to 3 hours or more.

Assessment of Mortality-Related Risk Factors and Effective Antimicrobial Regimens for Treatment of Bloodstream Infections Caused by Carbapenem-Resistant Enterobacterales

“…Herein, we found that combination therapy bene ts were only evident for therapeutic regimens not containing CAZ-AVI, whereas no differences were observed in patient survival when comparing CAZ-AVI monotherapy and combination regimens incorporating CAZ-AVI. Caston et al [28] and Mario Tumbarello et al [32] similarly found that CAZ-AVI-containing combination therapies were not linked to any improvements in the success of clinical treatment compared with CAZ-AVI monotherapy. As such, we posit that CAZ-AVI is a more promising therapeutic choice for treating patients infected with susceptible CRE isolates, even when used as a monotherapy.…”

An Evidence-Based Multidisciplinary Approach Focused at Creating Algorithms for Targeted Therapy of BSIs, cUTIs, and cIAIs Caused by Enterobacterales in Critically Ill Adult Patients

“…Very recently, Tumbarello et al analysed 577 patients with KPC-producing Klebsiella pneumoniae infections (67.8% with BSIs) treated with ceftazidime-avibactam. 75 No difference in mortality rate was found between ceftazidime-avibactam monotherapy vs combination therapy (26.1% vs 25.0%; p=0.79). Notably, ceftazidime-avibactam prolonged infusion resulted protective against mortality at multivariate analysis (p=0.006).…”

“… 76 These agents should be administered in prolonged or continuous infusion as well to maximize efficacy and clinical outcome. 75 , 109 Monotherapy with novel BL and BL/BLIs should always be pursued in these settings considering that comparative studies showed no significant advantage in efficacy of combination therapy vs monotherapy. 110 , 111 Against MBL-producers, the use of ceftazidime-avibactam plus aztreonam may represent an effective strategy for the management of NDM-producing Enterobacterales infections, whereas cefiderocol should be reserved mainly to VIM- or IMP-producing Enterobacterales infections.…”

Ceftazidime-Avibactam Therapy Versus Ceftazidime-Avibactam-Based Combination Therapy in Patients With Carbapenem-Resistant Gram-Negative Pathogens: A Meta-Analysis

“…The database search described in Database Search generated 17 eligible articles ( Sousa et al, 2018 ; Kuang et al, 2020 ; Guimarães et al, 2019 ; Rathish et al, 2021 ; Shields et al, 2018 ; Tumbarello et al, 2019 ; Ackley et al, 2020 ; Iannaccone et al, 2020 ; Castón et al, 2020 ; Tumbarello et al, 2021 ; Zhu et al, 2021 ; King et al, 2017 ; Temkin et al, 2017 ; De la Calle et al, 2019 ; Chen et al, 2020 ; Jiang et al, 2020 ; Jorgensen et al, 2020 ). Specifically, 1,106 references were found by searching for the keywords: “ceftazidime avibactam” and “carbapenem resistant.” After removing the duplicates, 667 potentially relevant articles were left.…”

“…There has been a dispute on whether monotherapy therapy would be inferior to combination therapy (15). Also, this debate occurred in the posttreatment CAZ-AVI scenario ( Shields et al, 2018 ; Tumbarello et al, 2019 ; Ackley et al, 2020 ; Castón et al, 2020 ; Iannaccone et al, 2020 ; Tumbarello et al, 2021 ).…”